Vanadium as a trace element is considered essential for animals; however it has not yet been recognized as a micronutrient for humans. Most of the information on the biological effects of vanadium was related to metal's insulin-like, anti-hyperlipidemic and anticancer properties in low concentrations. According to the previous literature, mitochondria were proposed as an important target for vanadium cytotoxicity. In this study, the mitochondrial toxicity mechanisms of sodium metavanadate (vanadium V or V(5+)) were investigated in the isolated mitochondria obtained from rat liver by differential centrifugation and mitochondrial toxicity endpoints as well as mitochondrial sources of ROS formation were determined in both in vivo and in vitro using specific substrates and inhibitors. Single injection of V(5+) into Wistar rat (10, 20 and 40 mg kg(-1), i.p.) caused a significant increase in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Isolated mitochondria from the V(5+)-treated rat liver showed a marked elevation in oxidative stress parameters accompanied by mitochondrial membrane potential (MMP) collapse as compared to a control group. On the other hand, our in vitro results with isolated mitochondria showed that different concentrations of V(5+) (25-200 μM) induced significant (P < 0.05) progress in mitochondrial ROS formation, ATP depletion, GSH oxidation, mitochondrial outer membrane rupture, mitochondrial swelling and cytochrome c release before the mitochondrial potential collapse ensued. We also showed that the V(5+) interaction with respiratory complex III is the major source of V(5+)-induced ROS formation. In general, our in vivo and in vitro data strongly supported that the V(5+)-induced liver toxicity is a result of the metal disruptive effect on the mitochondrial respiratory complexes I, II and III which are the obvious causes of metal-induced ROS formation and ATP depletion in liver cells which leads to cell death signalling via MPT pore opening and cytochrome c release.

Oxidative damage has been implicated in disorders associated with abnormal copper metabolism and also Cu(2+) overloading states. Besides, mitochondria are one of the most important targets for Cu(2+), an essential redox transition metal, induced hepatotoxicity. In this study, we aimed to investigate the mitochondrial toxicity mechanisms on isolated rat liver mitochondria. Rat liver mitochondria in both in vivo and in vitro experiments were obtained by differential ultracentrifugation and the isolated liver mitochondria were then incubated with different concentrations of Cu(2+). Our results showed that Cu(2+) induced a concentration and time-dependent rise in mitochondrial ROS formation, lipid peroxidation, and mitochondrial membrane potential collapse before mitochondrial swelling ensued. Increased disturbance in oxidative phosphorylation was also shown by decreased ATP concentration and decreased ATP/ADP ratio in Cu(2+)-treated isolated mitochondria. In addition, collapse of mitochondrial membrane potential (MMP), mitochondrial swelling, and release of cytochrome c following of Cu(2+) treatment were well inhibited by pretreatment of mitochondria with CsA and BHT. Our results showed that Cu(2+) could interact with respiratory complexes (I, II, and IV). This suggests that Cu(2+)-induced liver toxicity is the result of metal's disruptive effect on liver hepatocyte mitochondrial respiratory chain that is the obvious cause of Cu(2+)-induced ROS formation, lipid peroxidation, mitochondrial membrane potential decline, and cytochrome c expulsion which start cell death signaling.

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